Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

Matthews, Julie Marie; Bhatt, Shruti; Patricelli, Matthew P.; Nomanbhoy, Tyzoon; Jiang, Xiaoyu; Natkunam, Yasodha; Gentles, Andrew J.; Martinez, Ezequiel; Zhu, Daxing; Chapman, Jennifer R.; Cortizas, Elena M.; Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana H.; Li, Tan; Zhang, Jianming; Choi, Hwan Geun; Tibshirani, Robert; Buhrlage, Sara J.; Gratzinger, Dita; Verdún, Ramiro E.; Gray, Nathanael S.

doi:10.1182/blood-2016-02-696856

Cited by 20 publications

(14 citation statements)

References 41 publications

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“…S2D). Moreover, high-dose cyclophosphamide and alemtuzumab induced significantly greater BM tumor clearance than an R-CHOP regimen (30,31). Rituximab failed to induce apoptosis or phagocytosis by BM-derived macrophages (BMDM) in vitro ( Supplementary Fig.…”

Section: Alkylating Agents Overcome Therapeutic Resistance Of Human Lmentioning

confidence: 99%

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

et al. 2019

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The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fi de human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infi ltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identifi ed a "super-phagocytic" subset that expressed CD36/FCGR4. Together, these fi ndings defi ne a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. SIGNIFICANCE: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specifi c antibody resistance and defi ne an ER stress-dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types.

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Section: Alkylating Agents Overcome Therapeutic Resistance Of Human Lmentioning

confidence: 99%

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

et al. 2019

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“…We asked if copy number variations (CNV) and somatic mutations can be called robustly across the entire genome or exome, from cell free DNA (cfDNA) in patients with active disease, and if clonal somatic mutations and CNVs found in the bone marrow (BM) are reliably reproduced by cfDNA. We hypothesized that i) the subclonal composition of somatic mutations and CNVs differs, indicating that cfDNA and BM MM cells reveal distinct genetic information 6,7 , and ii) cfDNA can be used to track disease load and clonal evolution of MM, to provide longitudinal genetic information about disease evolution that is not accessible by bone marrow biopsy 8,9 .…”

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confidence: 99%

Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing

et al. 2018

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“…Several signaling pathways have been demonstrated to participate in autophagy regulation in solid cancers [25][26][27][28], but the mediated mechanisms in DLBCL still remains unknown. Previous research regarded the regulating pathways, mainly PI3K/AKT/mTOR and JNK signaling pathways, as the targeted treatment for DLBCL due to their positive regulation in further promotion of cell survival, proliferation, and drug resistance [2,29,30]. Hence, we hypothesized that CUL4B might be able to modulate autophagy via PI3K/AKT/mTOR or JNK pathway.…”

Section: Role Of Cul4b In Autophagy and Related Mechanismmentioning

confidence: 99%

“…With recent advancement of novel targeted therapy, such as monoclonal anti-CD20 antibody, the outcome of DLBCL patients have been significantly improved [1]. However, there are still 40~50% of DLBCL patients suffering relapse and eventually die from disease progression [2]. Therefore, searching more effective chemotherapeutic regimens for therapeutic management of DLBCL is warranted.…”

Section: Introductionmentioning

confidence: 99%

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Zhou

Zhang

et al. 2019

Cell Cycle

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Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identified that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL. ARTICLE HISTORY

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Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

Abstract: Key Points GCK signaling is activated in DLBCL, and this signaling is important to DLBCL proliferation and survival. Therapeutic targeting of GCK is feasible and may advance efforts to cure DLBCL patients.

Cited by 20 publications

References 41 publications

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents

Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

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